Germline Whole-Genome Sequencing in Early-Onset Pediatric Solid Tumors Implicates Novel Risk Factors
Matthew Nagy1,2, Andy Bhattacharjee3, Abigail Cinelli4
1Department of Pediatrics, Boston Children's Hospital/Harvard Medical School, Boston, MA.
JCO Precision Oncology
|June 3, 2026
Summary
Whole-genome sequencing (WGS) significantly increases the detection of rare germline variants in children with early-onset solid tumors, identifying new genetic risk factors and improving genetic risk assessment.
Area of Science:
- Genomics and Oncology
- Pediatric Cancer Genetics
- Rare Disease Research
Background:
- Many children with very early-onset solid tumors lack identified germline risk factors after standard genetic testing.
- Clinical genetic testing panels often miss large structural variants (SVs) and rare loss-of-function variants.
- Whole-genome sequencing (WGS) offers a more comprehensive approach to germline variant detection.
Purpose of the Study:
- To evaluate the diagnostic yield of germline whole-genome sequencing (WGS) in children with very early-onset solid tumors.
- To identify novel germline findings, including large SVs and loss-of-function variants, missed by panel testing.
- To assess the spectrum of germline alterations in this pediatric cancer cohort.
Main Methods:
- Retrospective cohort study of 132 children with very early-onset solid or brain tumors.
- Germline WGS performed on blood-derived DNA.
- Analysis focused on pathogenic variants in cancer predisposition genes (CPGs), large SVs, aneuploidies, and loss-of-function variants in highly constrained genes.
Main Results:
- Germline WGS increased the detection of pathogenic variants from 20% (panel testing) to 27%.
- Six percent of patients harbored large germline SVs or aneuploidies, including novel events.
- Rare loss-of-function variants were found in 35% of patients, and 50% overall carried a potentially pathogenic germline variant.
Conclusions:
- Germline WGS significantly enhances the detection of potentially pathogenic variants in early-onset solid tumors.
- WGS identifies novel structural and constrained-gene alterations, expanding the understanding of genetic susceptibility.
- These findings support the broader use of germline WGS for refined genetic risk assessment and discovery of new cancer mechanisms.
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